Relative contribution of genetic and nongenetic modifiers to intestinal obstruction in cystic fibrosis

Abstract

Background & aims: Neonatal intestinal obstruction (meconium ileus [MI]) occurs in 15% of patients with cystic fibrosis (CF). Our aim was to determine the relative contribution of genetic and nongenetic modifiers to the development of this major complication of CF.

Methods: A total of 65 monozygous twin pairs, 23 dizygous twin/triplet sets, and 349 sets of siblings with CF were analyzed for MI status, significant covariates, and genome-wide linkage.

Results: Specific mutations in the CF transmembrane conductance regulator (CFTR), the gene responsible for CF, correlated with MI, indicating a role for CFTR genotype. Monozygous twins showed substantially greater concordance for MI than dizygous twins and siblings (P = 1 x 10(-5)), showing that modifier genes independent of CFTR contribute substantially to this trait. Regression analysis revealed that MI was correlated with distal intestinal obstruction syndrome (P = 8 x 10(-4)). Unlike MI, concordance analysis indicated that the risk for development of distal intestinal obstruction syndrome in CF patients is caused primarily by nongenetic factors. Regions of suggestive linkage (logarithm of the odds of linkage >2.0) for modifier genes that cause MI (chromosomes 4q35.1, 8p23.1, and 11q25) or protect from MI (chromosomes 20p11.22 and 21q22.3) were identified by genome-wide analyses. These analyses did not support the existence of a major modifier gene on chromosome 19 in a region previously linked to MI.

Conclusions: The CFTR gene along with 2 or more modifier genes are the major determinants of intestinal obstruction in newborn CF patients, whereas intestinal obstruction in older CF patients is caused primarily by nongenetic factors.

Figure 1. Linkage peaks identified in 26 CF sibling pairs concordant for presence of MI

Shown are multipoint nonparametric LOD scores for linkage using the STR map (open circles) and SNP map (solid line) in 26 pairs with all CFTR genotypes included. The CFTR gene location on chromosome 7 is marked by the bar. For chromosome 4, also shown are linkage results from SNP genotyping in the subset of 20 MI-concordant pairs homozygous for ΔF508 (dashed line). For comparison of peak widths, 80 cM width is shown for each chromosome.

Figure 2. Linkage peaks identified in patients concordant for the absence of MI

Shown are multipoint nonparametric LOD scores for linkage using the STR map in 282 pairs with all CFTR genotypes included (open circles) and in the subset of 128 pairs without MI and homozygous for ΔF508 (filled circles). The CFTR gene location on chromosome 7 is marked by the bar. For comparison of peak widths, 80 cM width is shown for each chromosome.

Figure 3. Linkage analysis of the chromosome 19q13 region encompassing the CFM1 locus

(A) Entire chromosome 19, (B) the CFM1 region at chromosome 19q13. Shown are linkage results from the genome-wide STR map (open circles), the genome-wide SNP map (open triangles), and the chromosome 19-specific map of 7 STR markers (diamonds) which includes 5 STR markers used in a prior study of MI (17) and 2 additional STR markers (diamonds with asterisks). The region from 48–56 Mb encompasses 2 of the Marshfield STR markers, the 7 STR marker map, and 165 of the SNP markers. The location of CFM1 is indicated by the bar.